Roman Furtmüller

University of Belgrade, Belgrade, SE, Serbia

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Publications (28)102.64 Total impact

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    ABSTRACT: GABA(A) receptors mediate the action of many clinically important drugs interacting with different binding sites. For some potential binding sites, no interacting drugs have yet been identified. Here, we established a steric hindrance procedure for the identification of drugs acting at the extracellular α1+β3- interface, which is homologous to the benzodiazepine binding site at the α1+γ2- interface. On screening of >100 benzodiazepine site ligands, the anxiolytic pyrazoloquinoline 2-p-methoxyphenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 9895) was able to enhance GABA-induced currents at α1β3 receptors from rat. CGS 9895 acts as an antagonist at the benzodiazepine binding site at nanomolar concentrations, but enhances GABA-induced currents via a different site present at α1β3γ2 and α1β3 receptors. By mutating pocket-forming amino acid residues at the α1+ and the β3- side to cysteines, we demonstrated that covalent labeling of these cysteines by the methanethiosulfonate ethylamine reagent MTSEA-biotin was able to inhibit the effect of CGS 9895. The inhibition was not caused by a general inactivation of GABA(A) receptors, because the GABA-enhancing effect of ROD 188 or the steroid α-tetrahydrodeoxycorticosterone was not influenced by MTSEA-biotin. Other experiments indicated that the CGS 9895 effect was dependent on the α and β subunit types forming the interface. CGS 9895 thus represents the first prototype of drugs mediating benzodiazepine-like modulatory effects via the α+β- interface of GABA(A) receptors. Since such binding sites are present at αβ, αβγ, and αβδ receptors, such drugs will have a much broader action than benzodiazepines and might become clinical important for the treatment of epilepsy.
    Journal of Neuroscience 01/2011; 31(3):870-7. · 6.91 Impact Factor
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    ABSTRACT: Conflict procedures can be used to study the receptor mechanisms underlying the anxiolytic effects of benzodiazepines and other GABA(A) receptor modulators. In the present study, we first determined the efficacy and binding affinity of the benzodiazepine diazepam and recently synthesized GABA(A) receptor modulators JY-XHe-053, XHe-II-053, HZ-166, SH-053-2'F-S-CH₃ and SH-053-2'F-R-CH₃ at GABA(A) receptors containing α1, α2, α3 and α5 subunits. Results from these studies suggest that each compound displayed lower efficacy at GABA(A) receptors containing α1 subunits and varying degrees of efficacy and affinity at GABA(A) receptors containing α2, α3 and α5 subunits. Next, we assessed their anxiolytic effects using a rhesus monkey conflict procedure in which behavior was maintained under a fixed-ratio schedule of food delivery in the absence (non-suppressed responding) and presence (suppressed responding) of response-contingent electric shock. Relatively non-selective compounds, such as diazepam and JY-XHe-053 produced characteristic increases in rates of suppressed responding at low to intermediate doses and decreased the average rates of non-suppressed responding at higher doses. XHe-II-053 and HZ-166 also produced increases in suppressed responding at low to intermediate doses, but were ineffective at decreasing rates of non-suppressed responding, consistent with their relatively low efficacy at GABA(A) receptors containing α1 and α5 subunits. In contrast, SH-053-2'F-S-CH₃ and SH-053-2'F-R-CH₃ produced only partial increases in suppressed responding and were ineffective on non-suppressed responding, consistent with their profiles as partial agonists at GABA(A) receptors containing α2, α3 and α5 subunits. These behavioral effects suggest that the anxiolytic and rate-reducing effects of GABA(A) receptor positive modulators are dependent on their relative efficacy and affinity at different GABA(A) receptor subtypes.
    Neuropharmacology 12/2010; 59(7-8):612-8. · 4.11 Impact Factor
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    ABSTRACT: Over the last years, genetic studies have greatly improved our knowledge on the receptor subtypes mediating various pharmacological effects of positive allosteric modulators at GABA(A) receptors. This stimulated the development of new benzodiazepine (BZ)-like ligands, especially those inactive/low-active at GABA(A) receptors containing the alpha(1) subunit, with the aim of generating more selective drugs. Hereby, the affinity and efficacy of four recently synthesized BZ site ligands: SH-053-2'N, SH-053-S-CH3-2'F, SH-053-R-CH3-2'F and JY-XHe-053 were assessed. They were also studied in behavioral tests of spontaneous locomotor activity, elevated plus maze, and water maze in rats, which are considered predictive of, respectively, the sedative, anxiolytic, and amnesic influence of BZs. The novel ligands had moderately low to low affinity and mild to partial agonistic efficacy at GABA(A) receptors containing the alpha(1) subunit, with variable, but more pronounced efficacy at other BZ-sensitive binding sites. While presumably alpha(1) receptor-mediated sedative effects of GABA(A) modulation were not fully eliminated with any of the ligands tested, only SH-053-2'N and SH-053-S-CH3-2'F, both dosed at 30 mg/kg, exerted anxiolytic effects. The lack of clear anxiolytic-like activity of JY-XHe-053, despite its efficacy at alpha(2)- and alpha(3)-GABA(A) receptors, may have been partly connected with its preferential affinity at alpha(5)-GABA(A) receptors coupled with weak agonist activity at alpha(1)-containing subtypes. The memory impairment in water-maze experiments, generally reported with BZ site agonists, was completely circumvented with all four ligands. The results suggest that a substantial amount of activity at alpha(1) GABA(A) receptors is needed for affecting spatial learning and memory impairments, while much weaker activity at alpha(1)- and alpha(5)-GABA(A) receptors is sufficient for eliciting sedation.
    Progress in Neuro-Psychopharmacology and Biological Psychiatry 03/2010; 34(2):376-86. · 3.55 Impact Factor
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    ABSTRACT: Benzodiazepine site agonists or inverse agonists enhance or reduce gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated inhibition of neurons, respectively. Recently, it was demonstrated that the point mutation gamma 2F77I causes a drastic change in the affinity of a variety of benzodiazepine agonists or inverse agonists in receptor binding studies. Here we investigated the potency and efficacy of 10 benzodiazepine site ligands from 6 structural classes in wild-type and gamma 2F77I point mutated recombinant GABA(A) receptors composed of alpha 1 beta 3 gamma 2, alpha 2 beta 3 gamma 2, alpha 3 beta 3 gamma 2, alpha 4 beta 3 gamma 2, alpha 5 beta 3 gamma 2, and alpha 6 beta 3 gamma 2 subunits. Results indicate that the effects of the benzodiazepine site ligands zolpidem, zopiclone, Cl218872, L-655,708 and DMCM were nearly completely eliminated in all mutated receptors up to a 1 microM concentration. The effects of bretazenil, Ro15-1788 or abecarnil were eliminated in some, but not all mutated receptors, suggesting that the gamma 2F77I mutation differentially influences the actions of these ligands in different receptor subtypes. In addition, this point mutation also influences the efficacy of diazepam for enhancing GABA-induced chloride flux, suggesting that the amino acid residue gamma 2F77 might also be involved in the transduction of the effect of benzodiazepines from binding to gating. The application of these drugs in a novel mouse model is discussed.
    European journal of pharmacology 03/2010; 636(1-3):18-27. · 2.59 Impact Factor
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    ABSTRACT: Analogues of bicuculline devoid of the benzo ring fused to the lactone moiety were prepared by reacting 2-(tert-butyldimethylsiloxy)furans with 3,4-dihydroisoquinolinium salts. Some of these compounds (e.g., ROD185, 8) acted as modulators of the GABAA receptor, displacing ligands of the benzodiazepine binding site. They also strongly stimulated GABA currents mediated by recombinant GABAA receptors expressed in Xenopus oocytes.
    ChemInform 01/2010; 32(7).
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    ABSTRACT: The antiseizure activity of benzodiazepines (BDZs) 1-5 in mice and rats as animal models is described. These BDZs have selective efficacy for alpha2beta3gamma2 and alpha3beta3gamma2 GABA(A)-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.8-44 (mice, ip) were observed for compounds 2-4 in the subcutaneous metrazole seizure (scMET) test. In rats, orally (po) the TI was >5 to 105. These compounds represent novel leads in the search for anticonvulsants devoid of sedative, ataxic, and amnestic side effects.
    Journal of Medicinal Chemistry 04/2009; 52(7):1795-8. · 5.61 Impact Factor
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2009; 19.
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    ABSTRACT: 6,3'-Dinitroflavone (6,3'-DNF) is a synthetic flavone derivative that exerts anxiolytic effects in the elevated plus maze. Based on the finding that this effect is blocked by Ro15-1788 (ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate) which is a specific antagonist at the benzodiazepine binding site of GABA(A) receptors we investigated the interaction of 6,3'-DNF with several recombinant GABA(A) receptor subtypes. Inhibition of [(3)H]flunitrazepam binding to recombinant GABA(A) receptors in transiently transfected HEK293 cells indicated that 6,3'-DNF exhibited the highest affinity for GABA(A) receptors composed of alpha1beta2gamma2 subunits and a 2-20 fold lower affinity for homologous receptors containing alpha2, alpha3, or alpha5 subunits. Two-electrode voltage-clamp experiments in Xenopus oocytes indicated that 6,3'-DNF does not induce chloride flux in the absence of GABA, but exerts low efficacy inverse agonistic modulatory effects on GABA-elicited currents in the GABA(A) receptor subtypes alpha1beta2gamma2 and alpha5beta2gamma2. In the subtypes alpha2beta2gamma2, alpha3beta2gamma2, alpha4beta2gamma2, alpha6beta2gamma2 or alpha4beta2delta and alpha4beta3delta, 6,3'-DNF exerts either none or very low efficacy positive modulatory effects. In contrast, 100 nM Ro15-1788 exhibited weak to moderate partial agonistic effects on each receptor investigated. These data indicate that Ro15-1788 only can antagonize the weak inverse agonist effects of 6,3'-DNF on alpha1beta2gamma2 and alpha5beta2gamma2 receptors, but will enhance the weak agonistic effects on the other receptor subtypes investigated. The possible mechanism of the Ro15-1788 sensitive anxiolytic effect of 6,3'-DNF is discussed.
    European Journal of Pharmacology 09/2008; 591(1-3):142-6. · 2.59 Impact Factor
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    ABSTRACT: Ligands that bind to the benzodiazepine binding site on the GABA A receptor can attenuate or potentiate cognition. To investigate this property, the chemical determinants favoring selective binding or selective activation of the alpha5beta2gamma2 and alpha1beta2gamma2 GABA A receptor isoforms were examined. A 3D-pharmacophore, developed from a diverse set of BDZR ligands, was used as an initial basis for multivariate discriminant, fragment, and 3D-quantitative structure-activity relationship analyses, which formed the criteria for selection of additional compounds for study. We found that the electrostatic potential near the ligands' terminal substituent correlated with its binding selectivity toward the alpha5beta2gamma2 versus alpha1beta2gamma2 isoform; while the fragment length and frontier molecular orbital energetics correlated with a compounds influence on electrophysiological activity. Compounds with promising alpha5 profiles were further assessed for their ability to attenuate scopolamine-induced contextual memory impairment in mice. Surprisingly, both weak inverse agonist and antagonists that display binding selectivity toward the alpha5beta2gamma2 isoform were able to attenuate contextual memory impairment.
    Journal of Medicinal Chemistry 08/2008; 51(13):3788-803. · 5.61 Impact Factor
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    ABSTRACT: Benzodiazepine (BZ) site ligands affect vigilance, anxiety, memory processes, muscle tone and epileptogenic propensity through modulation of neurotransmission at GABA(A) receptors containing alpha1, alpha2, alpha3 or alpha5 subunits, and may have numerous experimental and clinical applications. The ability of non-selective BZ site inverse agonists to enhance cognition, documented in animal models and human studies, is clinically not feasible due to potentially unacceptable psychomotor effects. Most investigations to date have proposed the alpha1 and/or alpha5 subunit-containing GABA(A) receptors as comprising the memory-modulating population of these receptors. The novel ligand PWZ-029, which we synthesized and characterized electrophysiologically, possesses in vitro binding selectivity and moderate inverse agonist functional selectivity at alpha5-containing GABA(A) receptors. This ligand has also been examined in rats in the passive and active avoidance, spontaneous locomotor activity, elevated plus maze and grip strength tests, primarily predictive of the effects on the memory acquisition, basal locomotor activity, anxiety level and muscle tone, respectively. The improvement of task learning was detected at the dose of 5 mg/kg in the passive, but not active avoidance test. The inverse agonist PWZ-029 had no effect on anxiety or muscle tone, whereas at higher doses (10 and 20 mg/kg) it decreased locomotor activity. This effect was antagonized by flumazenil and also by the lower (but not the higher) dose of an agonist (SH-053-R-CH3-2'F) selective for GABA(A) receptors containing the alpha5 subunit. The hypolocomotor effect of PWZ-029 was not antagonized by the antagonist ss-CCt exhibiting a preferential affinity for alpha1-subunit-containing receptors. These data suggest that moderate negative modulation at GABA(A) receptors containing the alpha5 subunit is a sufficient condition for eliciting enhanced encoding/consolidation of declarative memory, while the influence of higher doses of modulators at these receptors on motor activity shows an intricate pattern whose relevance and mechanism await to be defined.
    Brain Research 06/2008; 1208:150-9. · 2.88 Impact Factor
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    ABSTRACT: Classical benzodiazepines (BZs) exert anxiolytic, sedative, hypnotic, muscle relaxant, anticonvulsive, and amnesic effects through potentiation of neurotransmission at GABA(A) receptors containing alpha(1), alpha(2), alpha(3) or alpha(5) subunits. Genetic studies suggest that modulation at the alpha(1) subunit contributes to much of the adverse effects of BZs, most notably sedation, ataxia, and amnesia. Hence, BZ site ligands functionally inactive at GABA(A) receptors containing the alpha(1) subunit are considered to be promising leads for novel, anxioselective anxiolytics devoid of sedative properties. In pursuing this approach, we used two-electrode voltage clamp experiments in Xenopus oocytes expressing recombinant GABA(A) receptor subtypes to investigate functional selectivity of three newly synthesized BZ site ligands and also compared their in vivo behavioral profiles. The compounds were functionally selective for alpha(2)-, alpha(3)-, and alpha(5)-containing subtypes of GABA(A) receptors (SH-053-S-CH3 and SH-053-S-CH3-2'F) or essentially selective for alpha(5) subtypes (SH-053-R-CH3). Possible influences on behavioral measures were tested in the elevated plus maze, spontaneous locomotor activity, and rotarod test, which are considered primarily predictive of the anxiolytic, sedative, and ataxic influence of BZs, respectively. The results confirmed the substantially diminished ataxic potential of BZ site agonists devoid of alpha(1) subunit-mediated effects, with preserved anti-anxiety effects at 30 mg/kg of SH-053-S-CH3 and SH-053-S-CH3-2'F. However, all three ligands, dosed at 30 mg/kg, decreased spontaneous locomotor activity, suggesting that sedation may be partly dependent on activity mediated by alpha(5)-containing GABA(A) receptors. Hence, it could be of importance to avoid substantial agonist activity at alpha(5) receptors by candidate anxioselective anxiolytics, if clinical sedation is to be avoided.
    Neuropsychopharmacology 02/2008; 33(2):332-9. · 8.68 Impact Factor
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    ABSTRACT: gamma-Aminobutyric acid, type A (GABA(A)) receptor alpha1 subunits containing a cysteine mutation at a position in the channel mouth (H109C) surprisingly formed a spontaneous cross-link with each other in receptors composed of alpha1H109C, beta3, and gamma2 subunits. Cross-linking of two alpha1H109C subunits did not significantly change the affinity of [(3)H]muscimol or [(3)H]Ro15-1788 binding in alpha1H109Cbeta3gamma2 receptors, but GABA displayed a reduced potency for activating chloride currents. On reduction of the disulfide bond, however, GABA activation as well as diazepam modulation was similar in mutated and wild-type receptors, suggesting that these receptors exhibited the same subunit stoichiometry and arrangement. Disulfide bonds could not be reoxidized by copper phenanthroline after having been reduced in completely assembled receptors, suggesting that cross-linking can only occur at an early stage of assembly. The cross-link of alpha1H109C subunits and the subsequent transport of the resulting homodimers to the cell surface caused a reduction of the intracellular pool of alpha1H109C subunits and a reduced formation of completely assembled receptors. The formation of alpha1H109C homodimers as well as of correctly assembled GABA(A) receptors containing cross-linked alpha1H109C subunits could indicate that homodimerization of alpha1 subunits via contacts located in the channel mouth might be one starting point of GABA(A) receptor assembly. Alternatively the assembly mechanism might have started with the formation of heterodimers followed by a cross-link of mutated alpha1 subunits at the heterotrimeric stage. The formation of cross-linked alpha1H109C homodimers would then have occurred independently in a separate pathway.
    Journal of Biological Chemistry 03/2007; 282(7):4354-63. · 4.65 Impact Factor
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    ABSTRACT: A successful unified pharmacophore/receptor model which has guided the synthesis of subtype selective compounds is reviewed in light of recent developments both in ligand synthesis and structural studies of the binding site itself. The evaluation of experimental data in combination with a comparative model of the alpha1beta2gamma2 GABA(A) receptor leads to an orientation of the pharmacophore model within the Bz BS. Results not only are important for the rational design of selective ligands, but also for the identification and evaluation of possible roles which specific residues may have within the benzodiazepine binding pocket.
    Current Medicinal Chemistry 02/2007; 14(26):2755-75. · 3.72 Impact Factor
  • European Neuropsychopharmacology - EUR NEUROPSYCHOPHARMACOL. 01/2007; 17.
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    ABSTRACT: The synthesis and in vitro affinity of the alpha5beta3gamma2 (alpha5) subtype selective BzR/GABA(A) antagonist 7 is described. This ligand is selective for alpha5 subtypes in vitro and is a potent antagonist of the effects of diazepam only at alpha5beta3gamma2 subtypes (oocytes). Ligands such as 7 will be important in the determination of which physiological function(s) are subserved by this GABA(A) alpha5 subtype.
    Journal of Medicinal Chemistry 01/2004; 46(26):5567-70. · 5.61 Impact Factor
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    ABSTRACT: 1,4-Addition of benzylamine to 2(5H)-furanone followed by dialkylation of the 3-position with allylbromide gave (+/-)-4-benzyl-3,3-diallyl-2(3H)-furanone (8), which served as the intermediate for the synthesis of various N-substituted 4-amino-3,3-dipropyl-2(3H)-furanones (+/-)-9a-l. The compounds were evaluated for their capacity to potentiate or inhibit GABA-evoked currents in Xenopus laevis oocytes expressing recombinant alpha1beta2gamma2 GABA(A) receptors. The benzyl, ethyl, and allyl carbamates ((R)-9a (100 microM), (+/-)-9b (100 microM), (+/-)-9c (200 microM)) stimulated GABA currents by 279 +/- 47%, 426 +/- 8%. and 765 +/- 61%, respectively, while the phenylcarboxamide (+/-)-9f (200 microM) stimulated currents by 420 +/- 33%. Concentration-response studies showed that compound 9c was approximately twice as potent in stimulating GABA currents as alpha-EMTBL (2), the most potent 3,3-dialkylbutyrolactone known to date. On the other hand, the N-sulfonyl analogues were much less active or even inhibited GABA-evoked currents. In vitro radioligand displacement studies on rat brain membranes showed that these compounds did not bind to the benzodiazepine or GABA recognition sites of the GABA(A) receptor. However, these compounds generally weakly displaced [(35)S]-TBPS (approximately 50% displacement at 100 microM), though potencies did not correlate with GABA current potentiation. Results obtained with alpha1beta1 and mutant alpha1beta2N265S receptors, which compared to alpha1beta2 receptors are both much less sensitive to current stimulation produced by the anticonvulsant loreclezole, suggest that at least some of these aminobutyrolactones, (e.g., 9a, 9c), and interestingly also alpha-EMTBL, share stimulatory properties with loreclezole.
    Journal of Medicinal Chemistry 07/2002; 45(13):2824-31. · 5.61 Impact Factor
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    ABSTRACT: Application of 4-(aminomethyl)cyclohexanecarboxylic acid (tranexamic acid; TAMCA) to the central nervous system (CNS) has been shown to result in hyperexcitability and convulsions. However, the mechanisms underlying this action are unknown. In the present study, we demonstrate that TAMCA binds to the gamma-aminobutyric acid (GABA) binding site of GABA(A) receptors in membranes from rat cerebral cortex and does not interfere with N-methyl-D-aspartate receptors. Patch-clamp studies using human embryonic kidney cells transiently transfected with recombinant GABA(A) receptors composed of alpha 1 beta 2 gamma 2 subunits showed that TAMCA did not activate these receptors but dose dependently blocked GABA-induced chloride ion flux with an IC(50) of 7.1 +/- 3.1 mM. Application of TAMCA to the lumbar spinal cord of rats resulted in dose-dependent hyperexcitability, which was completely blocked by coapplication of the GABA(A) receptor agonist muscimol. These results indicate that TAMCA may induce hyperexcitability by blocking GABA-driven inhibition of the CNS.
    Journal of Pharmacology and Experimental Therapeutics 05/2002; 301(1):168-73. · 3.89 Impact Factor
  • Journal of Medicinal Chemistry - J MED CHEM. 01/2002; 45(13):2824-2831.
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    ABSTRACT: We have recently identified a novel class of allosteric modulators of GABA(A) receptors, the ROD compounds that are structurally related to bicuculline. Here, the relationship of their site of action relative to other known modulatory sites of this receptor was investigated. Two types of ROD compounds, R1 (ROD164A, ROD185) and R2 (ROD222 and ROD259) could be differentiated. R1 compounds competitively inhibited binding of benzodiazepines in alpha1beta2gamma2 receptors, and their functional effects were partially inhibited by the benzodiazepine antagonist Ro15-1788 in a noncompetitive manner. The enhancement by an R1 compound was not additive with that by diazepam. R2 compounds in contrast failed to inhibit binding of benzodiazepines; the R2 compounds' functional effects were not inhibited by the benzodiazepine antagonist. The enhancement by an R2 compound was additive with that by diazepam. In contrast to benzodiazepines, both R1 and R2 type compounds were still able to enhance alpha1beta2 receptors. ROD164A in alpha1beta2gamma2 receptors was found to be partially antagonized by Ro15-1788 in a noncompetitive way. ROD178B did not affect gamma-aminobutyric acid induced currents, but was able to inhibit both enhancement by R1 and R2 type compounds as well as enhancement by diazepam. R1 and R2 type compounds as well as diazepam enhanced pentobarbital-induced currents in a Ro15-1788-sensitive way. We conclude that R1 type compounds act at the benzodiazepine binding site and additionally at a different R1 site, and that the R1, but not the R2 site is allosterically coupled to the benzodiazepine binding site. ROD178B is a competitive antagonist at the R1 site in that it shows allosteric interaction with the benzodiazepine binding site and displacement of benzodiazepines, and a negative allosteric modulator at the R2 site.
    Molecular Pharmacology 07/2001; 59(6):1470-7. · 4.41 Impact Factor
  • Journal of Medicinal Chemistry 12/2000; 43(23):4363-6. · 5.61 Impact Factor

Publication Stats

290 Citations
102.64 Total Impact Points

Institutions

  • 2008–2010
    • University of Belgrade
      • Faculty of Pharmacy
      Belgrade, SE, Serbia
  • 2007–2010
    • Medical University of Vienna
      • • Abteilung für Biochemie und Molekularbiologie
      • • Zentrum für Hirnforschung
      Vienna, Vienna, Austria
  • 1999–2010
    • University of Vienna
      • Brain Research Institute
      Wien, Vienna, Austria
  • 2004–2009
    • University of Wisconsin - Milwaukee
      • Department of Chemistry and Biochemistry
      Milwaukee, WI, United States
  • 2002
    • French National Centre for Scientific Research
      • Institut de Chimie des Substances Naturelles
      Paris, Ile-de-France, France